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YR2 LCRS Pharmacology > 19. Opioids > Flashcards

19. Opioids Flashcards

1
Q

what is an opiate?

A

an alkaloid that comes from the opium poppy

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2
Q

what are the 4 most common opiates?

A

morphine
codeine
thebaine
papaverine

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3
Q

what is the structure-activity relationship in morphine?

A

the tertiary nitrogen is important for the analgesic effect of morphine (it gives morphine its affinity and permits receptor anchoring)

if you extend the nitrogen side chain you go from agonist –> antagonist (it determines efficacy)

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4
Q

how do codeine and heroine work?

A

the hydroxyl groups associated with morphine are needed for activity so heroine and codeine need to be converted to morphine

heroine: conversion occurs in the brain
codeine: conversion occurs outside the brain

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5
Q

name 2 synthetic opioid drugs

A

methadone

fentanyl

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6
Q

why do methadone and fentanyl get into the brain better?

A

they are more lipid soluble so are able to cross the BBB more easily

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7
Q

describe the pharmacokinetics of opiates

A
  • given orally (therapeutic uses) or intravenously (abusive uses)
  • intravenous administration gives 100% bioavailability
  • heavily metabolised in the liver (first pass)
  • largely ionised in the blood (unionised form access tissues readily as it more lipophilic)
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8
Q

compare the lipid solubility of opioids

A

heroine is twice as soluble as morphine (and twice as potent)

codeine is a bit more lipid soluble than morphine but is considerably less potent

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9
Q

what is the relevance of the active metabolites of morphine produced?

A

morphine-6-glucoronide is the most potent active metabolite of morphine

morphine causes more of the negative side effects (e.g. respiratory depression) than metabolites

individuals who don’t metabolise morphine well are more likely to experience negative side effects

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10
Q

compare the metabolism of fentanyl and methadone

A

fentanyl has a fast metabolism (metabolised by cytochrome 3A4 quickly) whereas methadone has a slow metabolism (metabolised by several enzymes)

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11
Q

why is methadone used as heroine replacement?

A

as opposed to fentanyl it is cleared slowly and can accumulate in fatty tissues

it persists in the body for longer - takes 24hrs to clear

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12
Q

how is codeine metabolised?

A
  • metabolised by 2 cytochrome P450 enzymes
  • one enzyme activates codeine to morphine (5-10% is converted)
  • the other enzyme deactivates codeine in the liver
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13
Q

what are the pharmacodynamics of opioids?

A
  • they act via specific ‘opioid’ receptors
  • if you have an endogenous receptor, there is an endogenous agonist to influence physiology: endorphins, enkephalins, dynorphins/neoendorphins
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14
Q

what do the different endogenous agonists act on?

A
  1. endorphins act on mu or delta receptors in the cerebellum, caudate nucleus, nucleus accumbens and PAG - important in pain and sensation
  2. enkephalins act on delta receptors in the nucleus accumbens, cerebral cortex, hippocampus and putamen - important in motor and cognitive function
  3. dynorphins act on kappa receptors in the hypothalamus, putamen and caudate - important neuroendocrine role
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15
Q

what are the cellular actions of opiate receptors?

A
  • opioids are depressant so slow cellular activity
  • they can hyperpolarise cells (increase K+ efflux)
  • they can reduce the Ca2+ inward current
  • they can decrease adenylate cyclase activity
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16
Q

what effects do opioids have?

A
  • analgesia
  • euphoria
  • depression of cough centre
  • depression of respiration
  • stimulation of chemoreceptor trigger zone (nausea/vomiting)
  • pupillary constriction
  • GI effects
17
Q

how do opioids have an analgesic effect?

A
  • decrease pain perception
  • decrease amount of information relayed to the brain
  • increase pain tolerance
18
Q

outline the stages of pain detection

A
  1. pain is sensed peripherally
  2. recognised by sensory neurones
  3. info is relayed to the spinal cord
  4. spinothalamic neurones relay info to the brain (thalamus)
  5. the thalamus (gatekeeper) direct the info to the cortex
  6. the thalamus also directly activates the descending pain tolerance pathway, as does the cortex
  7. info is relayed to the NRM (effector arm)
  8. descending neurones leave to suppress feeling of pain that are reaching the brain
19
Q

what is the NRPG?

A

an auto-feedback element of the brain that allows pain tolerance to be switched on without any higher centre functioning at all

20
Q

how is the hypothalamus involved in pain detection?

A
  • the hypothalamus gives constant info to the rest of the brain about the current state of health
  • in a poorer state of health you are likely to be more sensitive to pain
  • sick people need to be in pain so they don’t expend their energy doing activities
21
Q

how is the locus coreleus involved in pain detection?

A
  • this is the sympathetic NS effector
  • if your stress pathway is activated, the LC is active –> automatic signal to dampen down pain
  • when you injure yourself during activity the SNS is active and suppresses pain information from the periphery to the brain
22
Q

what is the substantia gelatinosa?

A

a mini brain in the spinal cord where processing and modification of signals takes place

23
Q

how do opioids act on pain?

A
  • act in the dorsal horn to prevent information relay from the periphery to the spinothalamic tract (depressant)
  • disinhibit the normal inhibitory signal –> more pain tolerance
24
Q

how do opioids cause euphoria?

A
  • enter the brain and bind to receptors
  • depress the firing rate of GABA interneurones (disinhibition)
  • dopaminergic neurone firing rate increases –> increased dopamine secretion –> feelings of reward
25
Q

how does coughing occur?

A
  1. info is relayed to the brain that there is irritation in the throat/lungs
  2. afferent info reaches the cough centre in the medulla –> stimulates the effector arm (parasympathetic/motor nerves)
  3. parasympathetic/motor nerves innervate the diaphragm, IC muscles and lungs
  4. increased contraction of diaphragmatic, intercostal and abdominal muscles
  5. coughing
26
Q

what are the 2 neurotransmitters involved in coughing?

A

ACh and neurokinin

27
Q

why are 5-HT1A receptors important?

A

they are negative feedback receptors for serotonin

serotonin is anti-cough

5-HT1A receptors reduce the amount of serotonin that is available to suppress cough

28
Q

how do opioids have an effect on coughing?

A

they decrease the firing rate of neurones (C-fibres) which send info to the cough centre

they act in the cough centre with a direct depressant effect and inhibit 5-HT1A feedback receptors so more serotonin is available

29
Q

how do opioids cause respiratory depression?

A

inhibit the chemoreceptors (sensing the blood CO2 levels) and the pre-Botzinger complex

30
Q

how do opioids cause vomiting/nausea?

A

GABA keeps the chemoreceptor trigger zone (CTZ) suppressed, opioids switch off this inhibition

the CTZ signals to the medullary vomiting centre and you feel nauseous

31
Q

how do opioids cause miosis (pinpoint pupils)?

A

the optic nerve relays info to the pretectal nucleus

signals are transmitted to parasympathetic nerves in the edinger-westphal nucleus

GABA suppresses the parasympathetic nerves but opioids switch this inhibition off –> miosis

32
Q

how do opioids cause GI disturbance?

A

there are opioid receptors all over the enteric NS which prevent sensory info being relayed in

opioids also affect motor function –> heavy constipation due to suppression of enteric NS

less gut contraction and fewer secretions

33
Q

how do opioids cause urticaria (rash)?

A

opioids directly interact with mast cells causing histamine release

34
Q

how do you become tolerant to opioids?

A
  • opioids are constantly available –> cells are suppressed –> opioid receptors are withdrawn from the cell –> arrestin protein concentration increases (arrestin drives receptor internalisation) –> increased internalisation –> tolerance at tissue level
35
Q

how do you become dependent on opioids?

A

withdrawal is associated with psychological craving but there is also physical withdrawal (flu-like)

cells try to upregulate activity (increase in adenylate cyclase), once opioids are removed adenylate cyclase is overactive

36
Q

what are the signs of opioid overdose?

A
  • coma
  • respiratory depression
  • pinpoint pupils
  • hypotension
37
Q

how is opioid overdose treated?

A

naloxone (opioid antagonist) intravenously

YR2 LCRS Pharmacology (32 decks)

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